Deep brain stimulation (DBS) of the subthalamic nuclei (STN) substantially reduces motor symptoms in people with Parkinson disease (PD). However, STN DBS in PD also can alter cognitive control skills. How STN DBS improves motor function yet impairs cognition remains unclear but may depend upon organization of basal ganglia-thalamocortical pathways and their course through STN. Anatomic and physiologic studies in rats and non-human primates reveal differential connections of the dorsal region of STN (D-STN) compared to the ventral portion (V-STN).That combined with recent studies and clinical observations, including several from our lab, suggest that the motor action of STN DBS depends primarily on DBS of the D-STN or nearby structures and that DBS of V-STN impairs cognitive function. We have developed a novel method to precisely localize DBS contacts in the brain allowing us to investigate how DBS of these two regions of STN differentially affect motor and cognitive function, and how these alterations relate to DBS-induced neurophysiologic responses in the brain. Specifically, we hypothesize that DBS of D-STN provides maximal motor benefit whereas DBS of V-STN impairs cognitive control skills (e.g. working memory and response inhibition). We also hypothesize that these differences reflect alterations of downstream cortical areas selectively involved in motor (e.g. motor cortex and supplementary motor area) and cognitive function (dorsolateral prefrontal cortex and anterior cingulate). We will test these hypotheses by measuring regional cerebral blood flow, motor and cognitive responses to DBS of D-STN or V-STN in people with PD. We will determine if brain responses to DBS of different STN regions correlate with changes in motor or cognitive behavior. These studies could reveal valuable insights into the clinical action of DBS and the pathophysiology of cognitive as well as motor symptoms of PD. However, the importance of these studies goes beyond the specifics of DBS treatment for PD. We can take this unique opportunity to investigate the function of selected brain pathways in the region of the STN and how they affect motor and cognitive performance. Such basic observations have importance for understanding STN function and how impairments lead to disabilities in other basal ganglia disorders. These studies also have the potential to help refine targeting DBS, inform future development of new electrode design to shape current spread and improve programming strategies for optimal clinical benefit from STN DBS. PUBLIC HEALTH RELEVANCE: Parkinson disease (PD) affects nearly one million people in North American and leads to substantial disability for many. Deep brain stimulation (DBS) has been a dramatic advance, yet there are still many unknowns about how this new therapy works. This proposal has the potential to reveal valuable insights into the clinical action of DBS and the pathophysiology of non-motor as well as motor manifestations of PD. However, the importance of these studies goes well beyond the specifics of DBS treatment for PD. We also can take advantage of this unique opportunity to investigate the function of selected brain pathways and how they affect motor and cognitive performance. Such basic observations have importance for understanding normal function as well as how impairments lead to disabilities in other basal ganglia related disorders with motor or cognitive dysfunction.